chr10-110835878-C-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001134363.3(RBM20):c.3584C>A(p.Ser1195Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000246 in 1,550,564 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001134363.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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RBM20 | NM_001134363.3 | c.3584C>A | p.Ser1195Tyr | missense_variant | Exon 14 of 14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.3419C>A | p.Ser1140Tyr | missense_variant | Exon 14 of 14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.3200C>A | p.Ser1067Tyr | missense_variant | Exon 14 of 14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.3200C>A | p.Ser1067Tyr | missense_variant | Exon 14 of 14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.3584C>A | p.Ser1195Tyr | missense_variant | Exon 14 of 14 | 1 | NM_001134363.3 | ENSP00000358532.3 | ||
RBM20 | ENST00000465774.2 | n.525C>A | non_coding_transcript_exon_variant | Exon 2 of 2 | 4 | |||||
RBM20 | ENST00000480343.2 | n.217C>A | non_coding_transcript_exon_variant | Exon 3 of 3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.000328 AC: 50AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000278 AC: 42AN: 150986Hom.: 0 AF XY: 0.000249 AC XY: 20AN XY: 80330
GnomAD4 exome AF: 0.000237 AC: 332AN: 1398344Hom.: 1 Cov.: 30 AF XY: 0.000268 AC XY: 185AN XY: 689704
GnomAD4 genome AF: 0.000328 AC: 50AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:5
Reported in one patient with probable or definite statin-associated myopathy (PMID: 27296017); Also reported in individuals with left ventricular non-compaction (LVNC), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, additional cardiogenetic variants were identified in some cases (PMID: 32880476, 28798025, 26084686, 28087566, 30847666, 30775854); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32851336, 32880476, 30775854, 28087566, 30847666, 26084686, 28798025, 27296017) -
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Dilated cardiomyopathy 1DD Uncertain:2Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not specified Benign:1
Variant summary: RBM20 c.3584C>A (p.Ser1195Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 150986 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3584C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Left ventricular non-compaction (Miszalski-Jamka_2017, Verdonschot_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28798025, 32880476). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at